关键期后大鼠初级听皮层的可塑性及其机制研究

Functional development of the mammalian auditory system (particularly the primary auditory cortex, AI) is substantially influenced by auditory inputs during the critical period of early life stage when the system is most susceptible to alteration by acoustic experience. In the mature brain, however, it has been argued that acoustic inputs in conjunction with behavioral training or with stimulation of the basal forebrain system, is necessary to induce the persistent cortical changes. Recently, our studies have shown that passive exposure of adult animals to sound stimuli that lack instructive salient patterns also results in profound cortical tonotopic changes and more importantly, reestablishes a period of sound exposure-driven plasticity in their already mature AI. The main objective of this proposal is to reveal how sensory (acoustic) inputs might direct the passive sound exposure-driven plasticity in the post-critical period AI, by determining the consequence of continuous exposure to moderate-level band-limited noises beyond the critical period on different AI sectors (i.e., noise-exposed sectors or those representing the noise-free spectral bands) in rats. We will first examine the alteration in the frequency representation and neuronal response properties, including spectral tuning, intensity coding, and temporal responses in these different AI sectors induced by spectrally-limited noise exposure in post-critical period rats. Some of these noise-exposed rats will subsequently be exposed to a pulsed pure tone of specific frequency to explore the passive sound exposure-driven reorganization in their different AI sectors. We will also evaluate the post-exposure changes in the long-term potentiation (LTP) and the long-term depression (LTD) induced in brain slices from different AI sectors. By using quantitative immunoblotting, enzyme linked immunosorbent assay (ELISA), and immunohistochemical methods, we will finally quantify the post-exposure changes of certain molecules which might serve as mechanisms that underlay the reactivation of passive exposure-driven plasticity in different A1 sectors. Those molecules include the gamma-aminobutyric acid A (GABAA) receptor subunits α1, α3 and β2/3, N-methyl-D-aspartate (NMDA) receptor subunits NR2a and NR2b, and brain-derived neurotrophic factor (BDNF). The proposed research shall help us understand the mechanisms underlying the noise-induced plasticity in the post-critical period AI. In human populations, the developmental deficits in auditory function not only affect hearing in general, but also underlay poor language acquisition and reading skills in later life. Reactivation of plastic cortical reorganization in the post-critical period AI by the manipulation of acoustic inputs as proposed here in, could thus provide potential strategies for overcoming the developmentally degraded auditory information processing in older children and adults.

以发育关键期后大鼠为听觉实验模型，以初级听皮层 (AI) 的频率表达地形图、神经元频率调谐能力、强度编码能力和对连续声刺激的跟随能力等为指标，研究关键期后中等强度连续窄频噪音暴露对AI不同频率表达区 (即表达噪音频段的部位及其余部位) 神经元听反应的影响；以AI的频率表达地形图、调谐于特定频率的面积变化和听皮层脑片不同区域诱导的长时程增强及长时程抑制的幅值变化差异为指标，研究关键期后窄频噪音暴露诱导的AI不同频率表达区类似于关键期的可塑性变化并探讨其与暴露噪音频率 (即外部输入刺激参数) 之间的关系；采用蛋白印迹、酶联免疫吸附和免疫组织化学等生物化学技术，以抑制性GABAA 受体α1、α3和β2/3亚单位，兴奋性NMDA 受体NR2a和NR2b亚单位，以及脑源性神经营养因子 (BDNF) 的表达量和空间分布变化为指标，探讨关键期后AI类似于关键期可塑性变化的细胞分子机制。

本项目以大鼠为听觉实验动物模型，结合电生理及分子生物学技术探讨关键期后初级听皮层（Primary auditory cortex, AI）可塑性变化的神经机制。结果发现，关键期后中等强度连续窄频噪音暴露后，被窄频噪音频段覆盖的AI区听神经元的电生理反应特性明显有别于其余区域听神经元；连续窄频噪音暴露仅在AI区表达噪音频段的部位诱导出类似关键期的可塑性变化；该关键期后AI区的可塑性变化可能与其兴奋性和抑制性递质受体亚单位及脑源性神经营养因子（Brain-derived neurotrophic factor）和小白蛋白（Parvalbumin）等的表达变化有关。这些发现有助于深入理解关键期后中枢听觉系统可塑性的调控机制，对阐明脑发育可塑性原理也具普遍理论意义。本项目已发表4篇研究论文（包括2篇 Journal of Neuroscience，1篇 PNAS，以及1篇Cerebral Cortex）。以这些成果为主，题为《中枢听觉可塑性及其机制》的课题获得教育部高等学校自然科学奖二等奖。